Multiple interactions between the alpha 2C- and beta1-adrenergic receptors influence heart failure survival.
BACKGROUND
Persistent stimulation of cardiac beta1-adrenergic receptors by endogenous norepinephrine promotes heart failure progression. Polymorphisms of this gene are known to alter receptor function or expression, as are polymorphisms of the alpha 2C-adrenergic receptor, which regulates norepinephrine release from cardiac presynaptic nerves. The purpose of this study was to investigate possible synergistic effects of polymorphisms of these two intronless genes (ADRB1 and ADRA2C, respectively) on the risk of death/transplant in heart failure patients.


METHODS
Sixteen sequence variations in ADRA2C and 17 sequence variations in ADRB1 were genotyped in a longitudinal study of 655 white heart failure patients. Eleven sequence variations in each gene were polymorphic in the heart failure cohort. Cox proportional hazards modeling was used to identify polymorphisms and potential intra- or intergenic interactions that influenced risk of death or cardiac transplant. A leave-one-out cross-validation method was utilized for internal validation.


RESULTS
Three polymorphisms in ADRA2C and five polymorphisms in ADRB1 were involved in eight cross-validated epistatic interactions identifying several two-locus genotype classes with significant relative risks ranging from 3.02 to 9.23. There was no evidence of intragenic epistasis. Combining high risk genotype classes across epistatic pairs to take into account linkage disequilibrium, the relative risk of death or transplant was 3.35 (1.82, 6.18) relative to all other genotype classes.


CONCLUSIONS
Multiple polymorphisms act synergistically between the ADRA2C and ADRB1 genes to increase risk of death or cardiac transplant in heart failure patients.
Kardia
Sharon L R
SL
Department of Epidemiology, School of Public Health, University of Michigan, 109 Observatory St,, Ann Arbor, MI 48109-2029, USA. skardia@umich.edu
Kelly
Reagan J
RJ
Keddache
Mehdi A
MA
Aronow
Bruce J
BJ
Grabowski
Gregory A
GA
Hahn
Harvey S
HS
Case
Karen L
KL
Wagoner
Lynne E
LE
Dorn
Gerald W
GW
Liggett
Stephen B
SB
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D004843:Epistasis, Genetic; D005260:Female; D006333:Heart Failure / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology* / Q000601:surgery; D016027:Heart Transplantation; D006801:Humans; D053208:Kaplan-Meier Estimate; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016016:Proportional Hazards Models; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics* / Q000502:physiology; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics* / Q000502:physiology; D012307:Risk Factors; D013318:Stroke Volume; D016277:Ventricular Function, Left; D055815:Young Adult
C547774:ADRA2C protein, human; D018341:Receptors, Adrenergic, alpha-2; D018342:Receptors, Adrenergic, beta-1